Studies of inflammatory bowel disease (IBD) suggest that the basic abnormality consists of an unrestrained immunologic response, not to novel antigen, but rather to common antigens to which the mucosal system is ordinarily unresponsive. To gather data relevant to this hypothesis we have performed extensive studies of control lamina propria T cells. In initial studies we established that as compared to control peripheral blood T cells, lamina propria T cells manifest a greatly reduced response to stimulation via the TCR/CD3 pathway. This was true when cells were studied as a relatively unpurified form or when examined as highly purified CD4+ T cells. Responses via alternative pathways, i.e., via CD2 plus minus CD28 were also reduced, but not nearly so reduced as via TCR/CD3. In addition, the unresponsive state could be at least partially reversed by cultured cells in IL-2 alone (not IL-2 plus proliferative stimulus) for 24 hours; this suggested that the unrespon-siveness was a form of reversible anergy. In further studies, we examined the capacity of peripheral blood and lamina propria T cells to produce various cytokines under the above stimulation conditions. Here we found that both peripheral blood and lamina propria T cells produced relatively low amounts of IL-2, as well as IFN-gamma or Il-4, when stimulated via the TCR/CD3 pathway alone, but produced large amounts when stimulated via the CD2/CD28 co-stimulatory pathway. Thus, despite the fact that lamina propria T cells manifest greatly reduced proliferation, they produce as much or more cytokines, as compared to peripheral blood T cells. Finally, we performed studies to elucidate the mechanism of this form of "split" unresponsiveness. In particular, we crosslinked TCR/CD3 T cells under stringent conditions and did indeed induce T cell unresponsiveness (to subsequent stimulation via the TCR/CD3 pathway). However, such cells were also no longer responsive via the CD2 pathway either by proliferation or cytokine production. Thus, the unresponsiveness/responsiveness of lamina propria cells cannot yet be reproduced in culture. Overall, these studies reveal that lamina propria T cells achieve a unique functional state which allows them to act as effector cells in the local mucosal environment.